Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Retinal Sensitivity Using Microperimetry in Age-Related Macular Degeneration in an Amish Population

Muneeswar G. Nittala, MPhil Opt; Swetha Bindu Velaga, BS Opt; Amir Hariri, MD; Maximilian Pfau, MD; David G. Birch, PhD; Jonathan Haines, MD; Margaret A. Pericak-Vance, MD; Dwight Stambolian, MD; Srinivas R. Sadda, MD

Abstract

BACKGROUND AND OBJECTIVES:

To evaluate retinal sensitivity (RS) by mesopic and scotopic microperimetry (MP-1S) in an elderly Amish population with age-related macular degeneration (AMD).

PATIENTS AND METHODS:

Mesopic and scotopic microperimetric testing was performed in 148 eyes of 77 elderly Amish subjects (age > 50 years) from Pennsylvania using a retinal function analyzer. Scotopic testing was performed using a 2.0 log unit neutral density filter following 30 minutes of dark adaptation. All subjects underwent complete ophthalmic examinations, including spectral-domain optical coherence tomography, fundus autofluorescence, infrared reflectance imaging, and flash color fundus photography. Certified graders at Doheny Image Reading Center identified subjects with evidence of AMD as defined by the Beckman classification and quantified drusen volume. RS in subjects with and without AMD was compared. Correlations between RS and drusen burden were analyzed. Ten eyes with incomplete MP-1S exams were excluded from the final analysis.

RESULTS:

Among the 138 eyes from 77 subjects included in the final analysis, 42 eyes from 29 subjects had evidence of early or intermediate AMD. The mean age of subjects with AMD was 69.65 years ± 13.81 years versus 63.04 years ± 12.69 years in those without AMD (P = .06). Mesopic RS was 18.8 dB ± 2.1 dB in subjects with AMD and 19.6 dB ± 1.4 dB in those without AMD (P = .07). Scotopic RS was significantly lower (P = .04) in subjects with AMD (15.9 dB ± 2.9 dB) compared with those without AMD (17.3 dB ± 2.4 dB). There was no relationship between mesopic RS and either drusen area (r = −0.06; P = .32) or drusen volume (r = −0.08; P = .30). There was a trend for an association between scotopic RS and both drusen area (r = −0.39; P = .24) and drusen volume (r = −0.36; P = .30).

CONCLUSIONS:

In an elderly Amish population, eyes with early or intermediate AMD show a greater reduction in scotopic RS than mesopic RS, suggesting that rod function is more severely affected than cone function. Drusen area and volume measurements better correlated with scotopic RS.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:e236–e241.]

Abstract

BACKGROUND AND OBJECTIVES:

To evaluate retinal sensitivity (RS) by mesopic and scotopic microperimetry (MP-1S) in an elderly Amish population with age-related macular degeneration (AMD).

PATIENTS AND METHODS:

Mesopic and scotopic microperimetric testing was performed in 148 eyes of 77 elderly Amish subjects (age > 50 years) from Pennsylvania using a retinal function analyzer. Scotopic testing was performed using a 2.0 log unit neutral density filter following 30 minutes of dark adaptation. All subjects underwent complete ophthalmic examinations, including spectral-domain optical coherence tomography, fundus autofluorescence, infrared reflectance imaging, and flash color fundus photography. Certified graders at Doheny Image Reading Center identified subjects with evidence of AMD as defined by the Beckman classification and quantified drusen volume. RS in subjects with and without AMD was compared. Correlations between RS and drusen burden were analyzed. Ten eyes with incomplete MP-1S exams were excluded from the final analysis.

RESULTS:

Among the 138 eyes from 77 subjects included in the final analysis, 42 eyes from 29 subjects had evidence of early or intermediate AMD. The mean age of subjects with AMD was 69.65 years ± 13.81 years versus 63.04 years ± 12.69 years in those without AMD (P = .06). Mesopic RS was 18.8 dB ± 2.1 dB in subjects with AMD and 19.6 dB ± 1.4 dB in those without AMD (P = .07). Scotopic RS was significantly lower (P = .04) in subjects with AMD (15.9 dB ± 2.9 dB) compared with those without AMD (17.3 dB ± 2.4 dB). There was no relationship between mesopic RS and either drusen area (r = −0.06; P = .32) or drusen volume (r = −0.08; P = .30). There was a trend for an association between scotopic RS and both drusen area (r = −0.39; P = .24) and drusen volume (r = −0.36; P = .30).

CONCLUSIONS:

In an elderly Amish population, eyes with early or intermediate AMD show a greater reduction in scotopic RS than mesopic RS, suggesting that rod function is more severely affected than cone function. Drusen area and volume measurements better correlated with scotopic RS.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:e236–e241.]

Introduction

Age-related macular degeneration (AMD) is the most common cause of impaired visual function among the elderly in developed countries.1 Patients with late-stage AMD often complain of progressive vision loss, metamorphopsia, and scotoma.2 Early on, however, patients may have significant visual functional deficits that are not fully reflected in the visual acuity measurements.1,3 Other measurements of visual function beyond visual acuity (VA) have been evaluated in various retinal diseases, including AMD, and found to be potentially more useful to assess disease progression and monitor the effect of therapies.2,4,5 These functional tests may also have prognostic value by identifying patients at the highest risk of progression before the development of vision-threatening complications.3

Patients with early-stage AMD frequently complain of night blindness.6,7 Rod sensitivity is compromised in many retinal diseases including AMD. Histologic studies have found that rod damage can precede cone damage in eyes with early AMD.8,9 Thus, rod functional abnormalities appear before cone abnormalities,10,11 particularly at the parafoveal level where there are more rods.12,13 Previous studies have measured functional capacity of the macular photoreceptors in AMD using a variety of psychophysical techniques. Cone function has been assessed using contrast sensitivity,14,15 flicker sensitivity,16 focal cone electroretinogram,17 photopic light sensitivity test,18 and suprathreshold tests;19,20 rod function is measured by scotopic electroretinogram or by dark-adapted perimetry.21,22 These techniques do not allow a direct correlation of the functional deficits with the underlying anatomy. Macular microperimetry (MP) is a psychophysical method that measures retinal sensitivity (RS) with visualization of the underlying retina location.23,24 Previous studies have reported loss of retinal sensitivity in early AMD by mesopic MP25,26 and scotopic MP,6,10 but only in small selected cohorts presenting to retinal clinics.

The Amish Eye Study (AES) is a population-based study that is collecting multimodal imaging and functional testing data on a cohort of elderly Amish individuals, many of whom have early or intermediate AMD. In this report, we compare the scotopic and mesopic retinal sensitivity findings in these Amish subjects. We have intentionally focused on the Amish population because it is a founder population that represents an isolate with less genetic and environmental variation than outbred populations. As a result, the heterogeneity between individuals will be reduced. Additionally, the Amish do not indulge in significant smoking behavior, thereby eliminating this factor as an influence on AMD.

Patients and Methods

Enrollment of Amish subjects (77 subjects, 148 eyes) occurred between February 2013 and March 2016. The primary objective of the AES is to identify the risk factors for early AMD using multimodal retinal imaging. The prospective study protocols have been approved by the institutional review boards of the University of Pennsylvania and the University of California, Los Angeles. The study was conducted in accordance with the ethical standards as stated in the Declaration of Helsinki and the Health Insurance Portability and Accountability Act of 1996. Informed consent was obtained from all subjects after the nature and possible consequences of the study were explained. Inclusion criteria included age of 50 years or older, self-identification as Amish, and membership in a sibship with at least two individuals with AMD. The Amish are genetically and culturally isolated and experience a relatively uniform environment, reducing genetic diversity and variance in disease risk. Exclusion criteria included inadequate image quality or any previous or concomitant ophthalmological condition that could confound the interpretation of AMD features on imaging.

Study Procedures

All study subjects underwent a complete clinical examination, including an on-site ophthalmic examination, an interview, and venipuncture (for genetic testing, which was not a component of the analysis described in this report). Ophthalmic examination included best-corrected VA (BCVA), refraction, and fundus evaluation by indirect ophthalmoscopy and multimodal retinal imaging. Spectral-domain optical coherence tomography was performed using the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA), with macular cube scan protocols on both eyes, color fundus photography (Topcon fundus camera; Topcon Medical Systems, Oakland, NJ) and scotopic MP (MP-1S; Nidek Technologies, Padova, Italy) were also performed.

Microperimetry

The MP-1S uses a liquid crystal display rather than a laser for stimulus presentation and allows the examiner to select the number, intensity, and pattern of stimuli projected on the area of interest. With the MP-1S, the stimulus intensity is varied on a 1 (0.1 logarithmic)-step scale from 0 dB to 20 dB (400-4 apostilb, respectively). The computer-controlled system includes an autotracking system (25 times per second) to track fundus movements during the examination. All subjects underwent pupil dilation and after 20 minutes microperimetric testing was done under mesopic conditions. The subjects then waited in a dark room for 30 minutes before undergoing repeat testing under scotopic conditions.

Mesopic MP was performed in a dark room using stimulus size equivalent to a Goldmann V test spot with a grid of 32 stimuli covering a 20° area centered on the fovea and 4–2 double-staircase threshold strategy. The fixation target used for all participants was a 2° single cross or circle; stimuli were projected with a presentation time of 200 milliseconds, and a white background was used with illumination of 1.27 cd/m2.

For scotopic testing, the MP-1S was equipped with a short wavelength filter (50% cutoff = 502 nm) combined with a 1.0 or 2.0 log unit neutral density filter to selectively stimulate rods and to extend the dynamic range of the instrument to the very reduced illumination conditions required. The testing protocol was otherwise identical to the mesopic test. In the case of 10 eyes, the testing was terminated by the patient and/or operator before the completion of the microperimetric exam, and these cases were excluded from this analysis.

Analysis Strategy

Along with mean RS across the entire macula, we also calculated RS within the superior and inferior hemifields, as well as within rings of various sizes centered on the fovea (Figure 1). The goal of these analyses was to determine if there were any regional variations in the functional results. For the hemifield assessment, the test loci were divided by a horizontal plane passing through the foveal center. The mean sensitivities of loci superior to this plane were considered superior hemifield RS, and the mean of those below the plane was considered the inferior hemifield RS. For the ring analysis, mean sensitivities were computed for loci within 4° from the foveal center (inner ring), between 4° and 6° from the foveal center (middle ring), and between 6° and 10° from the center (outer ring; Figure 1).

Illustration of hemifield (A) and ring-wise (B) retinal sensitivity measurements.

Figure 1.

Illustration of hemifield (A) and ring-wise (B) retinal sensitivity measurements.

Statistical Analysis Methods

Statistical analyses were performed using SPSS version 18.0 for Windows (SPSS, Chicago, IL) on 138 eyes. Based on this sample, the study had power of 95% to detect a difference of 1 dB between groups. Classification of AMD was defined by the Beckman classification on fundus photographs.27 Drusen area and volume in the 5-mm circle from the center of the fovea were computed using Advanced RPE Analysis software in the Cirrus OCT.28,29 BCVA from Snellen chart was converted to logMAR units, and the data were used for statistical analysis. For continuous variables, the results were expressed as mean ± standard deviation (SD). Student's t-test was used for analyzing comparisons. Correlation between study parameters was performed using bivariate correlations. The generalized estimating equation method was used to adjust for correlations between eyes. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research.

Results

Of the 138 eyes from 77 subjects, 42 eyes from 29 subjects had evidence of early or intermediate AMD. The mean age of the 29 subjects with AMD was 69.65 years ± 13.81 years compared with 63.04 years ± 12.69 years in the elderly subjects without AMD; this difference was not statistically significant (P = .06). Mean RS was calculated by averaging the RS at each of 32 test locations. Age-adjusted mesopic RS (mean ± SD) was 18.8 dB ± 2.1 dB in subjects with AMD and 19.6 dB ± 1.4 dB in those without AMD; this difference was not statistically significant (P = .07).

For scotopic testing, however, the RS was 15.9 dB ± 2.9 dB in subjects with AMD versus 17.3 dB ± 2.4 dB in subjects without AMD (age adjusted). This apparent reduction in sensitivity was found to be statistically significant (P = .04,).

In subjects with AMD, the mean ± SD of the drusen area in the 5-mm circle was 1.17 ± 30.2 mm2, and drusen volume was 0.12 ± 0.41 mm3. The mean drusen area (r = −0.06; P = .32) and drusen volume (r = −0.08; P = .30) were poorly correlated with mesopic RS. Weak but nonsignificant correlations were found between scotopic RS and drusen area and volume (r = −0.39; P = .24 and r = −0.36; P = .30, respectively).

LogMAR VA was significantly lower (P = .02) in subjects with AMD (0.12 ± 0.21) than in those with no AMD (0.04 ± 0.16). LogMAR VA was negatively correlated with both mesopic (r = −0.55; P < .001) and scotopic (r = −0.47; P <.001) sensitivities.

Hemifield and Ring RS

Scotopic RS was significantly lower both superior (P = .02) and inferior (P = .04) to the fovea in subjects with AMD when compared with those with no AMD. In contrast, under mesopic conditions, RS was significantly lower in the superior hemifield (P = .03) but not in the inferior hemifield (P = .20) in those with AMD compared with those with no AMD (Table 1).

Correlation Between Superior, Inferior, and Ring-Wise Retinal Sensitivity Drusen Parameters

Table 1:

Correlation Between Superior, Inferior, and Ring-Wise Retinal Sensitivity Drusen Parameters

Mesopic RS within the foveal inner ring was significantly lower (P = .02) in AMD eyes compared with controls, but there was no significant difference in RS in the middle and outer rings (P = .09 and P = .06, respectively) between the AMD and no AMD groups. Interestingly, we found that the scotopic RS in the middle (P = .03) and outer (P = .01) rings was significantly reduced in subjects with AMD compared to those with no AMD (Table 2).

Comparison of Hemifields and Ring-Wise Retinal Sensitivity Between Study Groups

Table 2:

Comparison of Hemifields and Ring-Wise Retinal Sensitivity Between Study Groups

Correlations

Drusen volume was significantly correlated with scotopic RS of the inferior hemifield and inner, middle, and outer rings (r = −0.30, P = .004; r = −0.24, P = .03; r = −0.27, P = .01, and r = −0.24, P = .03, respectively), whereas drusen volume was not significantly correlated with hemifields and ring-wise mesopic RS (Table 1).

Discussion

In this study we report on mesopic and scotopic MP-derived RS measurements in elderly Amish subjects with and without AMD.

We observed that the scotopic RS was significantly lower in subjects with AMD compared with age-matched subjects without AMD, whereas no difference in sensitivity between groups could be identified under mesopic conditions. These observations would appear to confirm the observation that rod function is more severely affected than cone function in early or intermediate AMD. We know there is a constant decline in the number of rods in the adult eye.21,30,31 Our result agrees with recent histological studies on the preferential vulnerability of the rod system and the relative preservation of cone photoreceptors in early AMD.8,32,33 Furthermore, functional studies reported by Owsley et al.21 showed that scotopic sensitivity declines faster than photopic sensitivity throughout adulthood. Scholl et al.10 showed a consistent reduction in scotopic RS over areas of increased fundus autofluorescence (FAF), whereas the mesopic RS remained normal or was slightly reduced. This suggests that an increase of FAF, which may be observed during the evolution of AMD, is correlated with preferential dysfunction of the rod system.34

Of note, we observed no correlation between drusen volume and mesopic sensitivity across the macula, suggesting that in early and intermediate AMD drusen burden does not appear to have a significant impact on overall cone function. However, when considering the inner and middle rings alone, a significant negative correlation (ie, lower sensitivity with more drusen) was observed. Because large drusen tend to be more centrally oriented compared with reticular pseudodrusen, this observation may simply reflect the regional distribution of drusen. Interestingly, the inferior hemifield also appeared to demonstrate a significant correlation with drusen metrics for both mesopic and scotopic sensitivity. The reason for this is not immediately apparent. Future studies that consider not only the total drusen volume but its regional distribution may help better elucidate the explanation for this correlation.

Multifocal electroretinogram (mfERG) studies35,36 have demonstrated a significant delay in the average rod response in eyes with early AMD compared with normal healthy eyes, whereas the average cone-mediated responses were within the normal range. Because the mfERG response primarily reflects bipolar cell activity, it is not clear whether these delays originate from the level of the photoreceptors.36,37 Regardless, these studies support the suggestion that the rod pathway is more sensitive than the cone pathway to disruption in early AMD.

Our study has limitations. First, as with any psychophysical test, MP is a subjective test that requires a patient response. It is also subject to learning effects that may introduce a bias, whereas initial testing may reveal lower sensitivity values compared with a subject's true capability. As a result, the measurement is somewhat noisy. Having said that, our study represents one of the largest cohorts of microperimetric data in AMD subjects described to date. Another limitation of our study is that we quantified drusen but were not able to quantify pseudodrusen. Pseudodrusen are known to be associated with functional deficits and a poor prognosis in subjects with AMD. Pseudodrusen in this Amish cohort, however, were uncommon compared with many AMD populations38 and were generally located outside the MP test pattern. Our study also has many strengths, including its relatively large sample size for a microperimetry study, a relatively homogenous population in the Amish, and the use of certified reading center graders.

In summary, our results showed a greater reduction in scotopic RS than in mesopic RS in early AMD, indicating that rod dysfunction may precede cone dysfunction. Drusen measurements were better correlated with scotopic RS than with mesopic RS, although neither was statistically significant. Mean scotopic RS in the inferior hemifield and the inner and middle ring locations appeared to show the best correlation with drusen parameters. The significance of these findings needs to be evaluated in longitudinal studies.

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Correlation Between Superior, Inferior, and Ring-Wise Retinal Sensitivity Drusen Parameters

Drusen Area*, r (P)Drusen Volume*, r (P)

Mesopic RS (dB)Superior Hemifield−0.15 (.10)−0.12 (.20)
Inferior Hemifield−0.13 (.17)−0.13 (.17)
Inner Ring−0.29 (.14)−0.31 (.06)
Middle Ring−0.19 (.44)−0.16 (.07)
Outer Ring−0.09 (.33)−0.07 (.44)

Scotopic RS (dB)Superior Hemifield−0.23 (.08)−0.20 (.06)
Inferior Hemifield−0.34 (.001)−0.30 (.004)
Inner Ring−0.26 (.01)−0.24 (.03)
Middle Ring−0.31 (.003)−0.27 (.01)
Outer Ring−0.27 (.01)−0.24 (.03)

Comparison of Hemifields and Ring-Wise Retinal Sensitivity Between Study Groups

No AMD, Mean ± SD (Range)AMD, Mean ± SD (Range)P

Mesopic RS (dB)Superior Hemifield19.54 ± 1.38 (11.00–20.00)18.33 ± 3.27 (0.89–20.00).03
Inferior Hemifield19.76 ± 1.59 (6.29–20.00)19.09 ± 3.15 (1.43–20.00).2
Inner Ring19.73 ± 1.42 (9.50–20.00)18.58 ± 3.80 (0.00–20.00).07
Middle Ring19.67 ± 1.57 (7.50–20.00)18.82 ± 3.07 (3.00–20.00).09
Outer Ring19.59 ± 1.32 (9.88–20.00)18.55 ± 3.28 (0.00–20.00).06

Scotopic RS (dB)Superior Hemifield17.01 ± 2.25 (7.67– - 19.89)15.65 ± 3.04 (7.70–20.00).02
Inferior Hemifield17.68 ± 2.69 (4.14–20.00)16.33 ± 2.94 (9.57–20.00).04
Inner Ring16.38 ± 3.17 (3.75–20.00)15.13 ± 3.22 (8.25–20.00).1
Middle Ring17.62 ± 2.43 (5.25–20.00)16.23 ± 2.74 (10.67–20.00).03
Outer Ring17.29 ± 2.22 (7.38–19.88)15.87 ± 3.07 (7.00–20.00).02
Authors

From Doheny Image Reading Center, Doheny Eye Institute, Los Angeles (MGN, SBV, AH, MP, SRS); Retina Foundation of the Southwest, Dallas (DGB); the Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland (JH); John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, (MAP-V); the Department of Ophthalmology, University of Pennsylvania, Perelman School of Medicine, Philadelphia (DS); and the Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles (SRS).

Presented at the Association for Research in Vision and Ophthalmology 2015, Seattle.

Supported by R01 EY023164 (DS), R01 EY 09076 (DGB), the Department of Ophthalmology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (DS), the Foundation Fighting Blindness (DGB), and the F.M. Kirby Foundation (DS) and Research to Prevent Blindness (DS).

Dr. Sadda has received personal fees from Allergan, Iconic Therapeutics, Novartis, ThromboGenics, Genentech, Heidelberg Engineering, Topcon, CenterVue, and NightstaRx. The remaining authors report no relevant financial disclosures.

Address correspondence to SriniVas R. Sadda, MD, President and Chief Scientific Officer, Doheny Eye Institute, P.O. Box 86228, Los Angeles, CA 90033; email: ssadda@doheny.org.

Received: May 18, 2018
Accepted: March 22, 2019

10.3928/23258160-20190905-15

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